Our long-term goal is to ameliorate the debilitating consequences of age-related hearing loss (ARHL) or presbycusis. ARHL is the number one communication disorder and number one neurodegenerative condition of our expanding aging population. The vast majority of people over age 60 are affected by this progressive decline in auditory sensitivity and difficulty understanding speech in noise. While ARHL is one of the top three chronic medical conditions of the elderly, there currently are no approved medical treatments for preventing or reversing permanent hearing loss (ARHL or other types). Despite decades of research and discovery, overcoming the barriers of ARHL through prevention and treatment continues to represent a major scientific and clinical challenge. The thematic focus of this application is modulation of presbycusis through biotherapeutics and targeted induction of neural plasticity. An important feature of these approaches is elucidating the related roles of peripheral function and central auditory plasticity in auditory processing. This pioneering research uses innovative catalysts to induce functional changes in the aging auditory system. We target the primary consequences of ARHL using an array of measurement techniques in animal and human subjects. Insights gained from the evaluation of current theoretical models and project-specific hypotheses will play a prominent role in guiding development of new behavioral, technological and medical treatments aimed at slowing or preventing the progression of ARHL. Specific Aim 1. Determine the degree to which hormonal supplementation can prevent or slow the progression of ARHL. Experimental approach: Serum aldosterone and other related metrics and biomarkers will be quantitatively measured along with behavioral, physiological, and molecular indices, including peripheral and central hearing measures, in aging subjects undergoing aldosterone hormone therapies. Specific Aim 2. Determine the ability of enriched acoustic environments to ameliorate presbycusis. Experimental approach: Enriched acoustic environments will consist of extended, controlled exposure to specific artificially generated sounds presented in the free field in the animal holding environment (mouse vivarium facility) and via custom ear-level hearing instruments in humans. Outcome measures will index peripheral and central components of key features and biomarkers of ARHL. Specific Aim 3. Determine relations between brain plasticity and ARHL in older humans and animals, including the neural and molecular mechanisms that are involved. Experimental approach: We will build upon work indicating that reduced central inhibition and/or plastic changes in cortical activity ar key components of ARHL. A major focus of experiments will be the link between ARHL and central neural inhibition and excitation, particularly in older human and animal subjects.